Mitochondria control a number of specialized cellular processes that are essential for energy production, fat metabolism, steroid synthesis, and programmed cell death-pathways that are also critical for carcinogenesis. The goal of this application is to identify mitochondrial genes and their pathways that influence the risks of breast and prostate cancer among a diverse population of African American, Japanese American, Native Hawaiian, Latino and White men and women. We propose in Aim 1 to examine the association between mitochondrial genes and pathways encoded by both the nuclear and mitochondrial genomes for their impact on breast and prostate cancer, utilizing innovative gene set enrichment analysis (GSEA) approaches. Mitochondrial genes and nuclear regulators of mitochondrial activity will be identified from a comprehensive catalog of mitochondrial proteins based on computational genomics, protein biochemistry, and imaging. We will test these mitochondrial genes, leveraging existing nuclear and mitochondrial genome-wide SNP data, from our large case-control studies of breast (2,241 cases, 2,863 controls) and prostate cancer (3,634 cases, 3,713 controls) nested within the Multiethnic Cohort (MEC). Aim 2 will evaluate whether genes are modified by disease sub-groups (stage, grade, ER+/- breast tumors), environmental factors related to mitochondrial activity (smoking, BMI, fat, carotenoids, vitamin C, vitamin E, iron, lycopene and selenium) and susceptibility loci for breast and prostate cancer identified by genome-wide association studies. The strengths of this application include: 1) the use of innovative and sophisticated analytical methods; 2) the strong investigative team; 3) the efficient use of existing genetic and epidemiologic resources; and 4) the scientific and public health significance, especially in regards to understudied minority populations. The knowledge gained by this study may extend our understanding of the underlying genetic factors that contribute to breast and prostate cancers, and may lead to key insight into the biologic pathways of cancer development. The ultimate application of these findings may improve the prevention, diagnosis and treatment of cancers of the breast and prostate.